Somatic and terminal CB1 receptors are differentially coupled to voltage-gated sodium channels in neocortical neurons.

Endogenous cannabinoid signaling is vital for important brain functions, and the same pathways can be modified pharmacologically to treat pain, epilepsy, and posttraumatic stress disorder. Endocannabinoid-mediated changes to excitability are predominantly attributed to 2-arachidonoylglycerol (2-AG) acting presynaptically via the canonical cannabinoid receptor, CB1. Here, we identify a mechanism in the neocortex by which anandamide (AEA), another major endocannabinoid, but not 2-AG, powerfully inhibits somatically recorded voltage-gated sodium channel (VGSC) currents in the majority of neurons.

Direct whole-cell patch-clamp recordings from small boutons in rodent primary neocortical neuron cultures.

Direct electrical recordings from conventional boutons in the mammalian central nervous system have proven challenging due to their small size. Here, we provide a protocol for direct whole-cell patch-clamp recordings from small presynaptic boutons of primary dissociated cultured neurons of the rodent neocortex. We describe steps to prepare primary neocortical cultures and recording pipettes, followed by identifying boutons and establishing a whole-cell bouton recording.

Enhanced excitability of cortical neurons in low-divalent solutions is primarily mediated by altered voltage-dependence of voltage-gated sodium channels.

Increasing extracellular [Ca2+] ([Ca2+]o) strongly decreases intrinsic excitability in neurons but the mechanism is unclear. By one hypothesis, [Ca2+]o screens surface charge, reducing voltage-gated sodium channel (VGSC) activation and by another [Ca2+]o activates Calcium-sensing receptor (CaSR) closing the sodium-leak channel (NALCN). Here we report that neocortical neurons from CaSR-deficient (Casr-/-) mice had more negative resting potentials and did not fire spontaneously in reduced divalent-containing solution (T0.

Large, Stable Spikes Exhibit Differential Broadening in Excitatory and Inhibitory Neocortical Boutons.

Presynaptic action potential spikes control neurotransmitter release and thus interneuronal communication. However, the properties and the dynamics of presynaptic spikes in the neocortex remain enigmatic because boutons in the neocortex are small and direct patch-clamp recordings have not been performed. Here, we report direct recordings from boutons of neocortical pyramidal neurons and interneurons.

Diadenosine-Polyphosphate Analogue AppCH2ppA Suppresses Seizures by Enhancing Adenosine Signaling in the Cortex.

Epilepsy is a multifactorial disorder associated with neuronal hyperexcitability that affects more than 1% of the human population. It has long been known that adenosine can reduce seizure generation in animal models of epilepsies. However, in addition to various side effects, the instability of adenosine has precluded its use as an anticonvulsant treatment.